The serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multifactorial protein, induces a number of effects on platelets, endothelial cells, smooth muscle cells, leukocytes, the heart, and neurons. Activation of the coagulation cascade through either the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage to vessel walls or tissue factor release) leads to a series of biochemical events that converge on thrombin. Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolytic cleavage of the cell surface thrombin receptor, and autoamplifies its own production through a feedback mechanism. Thus, inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases.
In vivo diagnostic imaging methods for intravascular thrombi have been previously reported. These imaging methods use compounds that are detectably labeled with radioactive or paramagnetic atoms. For example, platelets labeled with the gamma emitter, In-111, can be employed as an imaging agent for detecting thrombi. In addition, the use of the paramagnetic contrasting agent, gadolinium diethylenetriaminepentaacetic acid in magnetic resonance imaging of patients treated by thrombolysis for acute myocardial infarction has been reported.
A need continues to exist for non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side-effects than currently available protease inhibitors. Accordingly, new protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian proteolytic disease states.
The oxidation of pyridines and other N-containing heteroaryls such as pyrimidines, quinolines, pyrazines, benzoxadiazoles, and pyridazinoquinolines to their N-oxides is sometimes employed in drug discovery programs. Numerous methods have been developed to effect this transformation. In many cases, this transformation can be accomplished using a peracid such as, meta-chloroperbenzoic acid, magnesium monoperphthalate, or a peracid formed in situ from, for example, 30% aqueous hydrogen peroxide and trifluoroacetic anhydride or acetic anhydride. Some electron deficient pyridines can be oxidized using catalytic MTO (MeReO3) and 30% H2O2 as the co-oxidant, or trifluoroacetic anhydride and hydrogen peroxide-urea complex (Tet. Lett. 41:2299, 2000), or peroxysulfuric acid formed in situ from Oxone® and sulfuric acid (J. Org. Chem. 42:1869, 1977). It is not unusual to encounter difficulties in transforming highly electron deficient pyridines to N-oxides using above methods; see, for example, Tet. Lett. 41:2299, 2000. The need exists for a practical method for the oxidation of highly electron deficient nitrogen containing heteroaryls to their N-oxides.